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one marrow more reference expression data biogps more reference expression data gene ontology molecular function calcium ion binding protein binding transmembrane signaling receptor activity carbohydrate binding protein homodimerization activity cellular component integral component of membrane integral component of plasma membrane membrane external side of plasma membrane protein containing complex cell surface biological process signal transduction sources amigo quickgo orthologs databases ncbi entry oma entry species human mouse entrez 969 12515 ensembl ensg00000110848 ensmusg00000030156 uniprot q07108 p37217 refseq mrna nm_001781 nm_001033122 refseq protein np_001772 np_001028294 location ucsc chr 12 9 75 9 76 mb chr 6 129 24 129 25 mb pubmed search 3 4 wikidata view edit human view edit mouse cd69 c luster of d ifferentiation 69 is a human transmembrane c type lectin protein encoded by the cd69 gene it is an early activation marker that is expressed in hematopoietic stem cells t cells and many other cell types in the immune system 5 it is also implicated in t cell differentiation as well as lymphocyte retention in lymphoid organs function edit the activation of t lymphocytes and natural killer nk cells both in vivo and in vitro induces expression of cd69 this molecule which appears to be the earliest inducible cell surface glycoprotein acquired during lymphoid activation is involved in lymphocyte proliferation and functions as a signal transmitting receptor in lymphocytes including natural killer nk cells and platelets cambiaggi et al 1992 supplied by omim 6 structure and ligands edit the gene encoding cd69 is located in the nk gene complex on chromosome 6 and chromosome 12 in mice and humans respectively 7 activation signaling pathways in lymphocytes nk cells dendritic cells and other cell types upregulate transcription factors such as nf κb erg 1 erythroblast transformation specific related gene 1 and ap 1 activator protein in order to promote the transcription of the cd69 gene 8 7 the cd69 protein is subject to post translational modifications namely it is differentially glycosylated to produce either a 28 kda peptide or a 32 kda peptide two of these peptides randomly combine to form a homodimer linked by a disulfide bond 7 these subunits have a c type lectin domain ctld that binds ligands a transmembrane domain and a cytoplasmic tail that relays signals to the cell interior 7 cd69 lacks the characteristic ca 2 binding residues in ctlds indicating that it might bind to proteins rather than carbohydrates the usual ligand of ctlds 9 7 it has been shown that cd69 binds to gal 1 a carbohydrate binding protein located on some dendritic cells and macrophages in addition to myl9 12 8 other ligands have yet to be identified however it is known that binding of the ligands initiates the jak stat signaling pathway as well as the mtor hif1 α pathway 9 8 7 cd69 is also known to interact with and mediate s1p and lat1 receptors which influence lymphocyte egress in lymphoid organs among other responses 10 8 more work must be done to fully characterize cd69 ligand interactions as well as cd69 s method of transducing intracellular signals t cell differentiation edit cd69 expression has been associated with both regulatory t cell treg memory t cell and bcl6 lo cd69 hi lz gc b plasmablast precursors 11 treg precursors exit the thymus expressing cd69 and complete differentiation into treg cells in peripheral tissues when they encounter antigens and other cytokines like il 2 12 through the jak stat signaling pathway cd69 activation also induces the production of tgf β as well as il 2 which contribute to the differentiation of treg cells as mentioned above 8 furthermore cd69 is also known to be upregulated by nf κb signaling at the onset of an immune response a prolonged immune response is then maintained by the non canonical nf κb pathway which in turn is associated with treg differentiation 7 in addition to treg differentiation cd69 is a common marker of precursor and mature resident memory t cells trms that are localized in peripheral tissues 13 9 tgf β is also responsible for the development of trms thus promoting trm differentiation in a manner similar to treg differentiation 14 lymphocyte migration edit most lymphocytes express sphingosine 1 phosphate receptors s1p1 5 which are g protein coupled receptors located in the cell membrane that bind to the ligand sphingosine 1 phosphate s1p s1p is a sphingolipid metabolite that is abundant in the bloodstream and upon binding to s1pr1 promotes lymphocyte egress from lymphoid organs so they can travel to affected tissues 15 8 however when a t cell is activated in a lymphoid organ through cytokine and tcr signaling cd69 is expressed and forms a complex with s1pr1 not s1pr3 or s1pr5 this association is dependent on the interaction between the cd69 transmembrane domain and helix 4 of s1pr1 following formation of this complex s1pr1 is internalized and is destroyed within the cell inhibiting its ability to bind s1p and initiate downstream signaling this in turn results in temporary lymphocyte retention in the lymph organs 8 it is thought that retention of lymphocytes in the lymph nodes may increase the chance of successful lymphocyte activation especially if the initial activation signal was weak similarly cd69 expressed in thymocytes following positive selection may ensure that t cells fully mature in the thymus prior to entering circulation 10 some research has shown that s1pr1 and cd69 co regulate so that when cd69 is in greater abundance it results in the removal of s1pr1 from the membrane as mentioned above 10 however if s1pr1 is more abundant than cd69 as would be the case in mature t cells cd69 membrane localization is reduced in this manner regulation of cd69 and s1pr1 expression and localization jointly impact lymphocyte egress and migration 10 see also edit cluster of differentiation references edit 1 2 3 grch38 ensembl release 89 ensg00000110848 ensembl may 2017 1 2 3 grcm38 ensembl release 89 ensmusg00000030156 ensembl may 2017 human pubmed reference national center for biotechnology information u s national library of medicine mouse pubmed reference national center for biotechnology information u s national library of medicine ziegler sf ramsdell f alderson mr september 1994 the activation antigen cd69 stem cells 12 5 456 65 doi 10 1002 stem 5530120502 pmid 7804122 s2cid 22182832 entrez gene cd69 cd69 molecule 1 2 3 4 5 6 7 radulovic k niess jh 2015 cd69 is the crucial regulator of intestinal inflammation a new target molecule for ibd treatment journal of immunology research 2015 497056 doi 10 1155 2015 497056 pmc 4352431 pmid 25759842 1 2 3 4 5 6 7 cibrián d sánchez madrid f june 2017 cd69 from activation marker to metabolic gatekeeper european journal of immunology 47 6 946 953 doi 10 1002 eji 201646837 pmc 6485631 pmid 28475283 1 2 3 kimura my hayashizaki k tokoyoda k takamura s motohashi s nakayama t july 2017 crucial role for cd69 in allergic inflammatory responses cd69 myl9 system in the pathogenesis of airway inflammation immunological reviews 278 1 87 100 doi 10 1111 imr 12559 pmid 28658550 s2cid 4327394 1 2 3 4 cyster jg schwab sr 2012 sphingosine 1 phosphate and lymphocyte egress from lymphoid organs annual review of immunology 30 69 94 doi 10 1146 annurev immunol 020711 075011 pmid 22149932 ise wataru april 17 2018 t follicular helper cell germinal center b cell interaction strength regulates entry into plasma cell or recycling germinal center cell fate immunity 48 4 702 715 e4 doi 10 1016 j immuni 2018 03 027 pmid 29669250 gonzález amaro r marazuela m april 2016 t regulatory treg and t helper 17 th17 lymphocytes in thyroid autoimmunity endocrine 52 1 30 8 doi 10 1007 s12020 015 0759 7 pmid 26475497 s2cid 30154540 farber dl yudanin na restifo np january 2014 human memory t cells generation compartmentalization and homeostasis nature reviews immunology 14 1 24 35 doi 10 1038 nri3567 pmc 4032067 pmid 24336101 mueller sn mackay lk february 2016 tissue resident memory t cells local specialists in immune defence nature reviews immunology 16 2 79 89 doi 10 1038 nri 2015 3 pmid 26688350 s2cid 3155731 garris cs blaho va hla t han mh july 2014 sphingosine 1 phosphate receptor 1 signalling in t cells trafficking and beyond immunology 142 3 347 53 doi 10 1111 imm 12272 pmc 4080950 pmid 24597601 further reading edit li q lan x han x wang j january 2019 expression of tmem119 sall1 and ccr2 cd69 in facs sorted microglia and monocyte macrophage enriched cell populations after intracerebral hemorrhage front cell neurosci 12 520 doi 10 3389 fncel 2018 00520 pmc 6333739 pmid 30687011 cambiaggi c scupoli mt cestari t gerosa f carra g tridente g accolla rs 1992 constitutive expression of cd69 in interspecies t cell hybrids and locus assignment to human chromosome 12 immunogenetics 36 2 117 20 doi 10 1007 bf00215288 pmid 1612643 s2cid 20364822 lópez cabrera m muñoz e blázquez mv ursa ma santis ag sánchez madrid f september 1995 transcriptional regulation of the gene encoding the human c type lectin leukocyte receptor aim cd69 and functional characterization of its tumor necrosis factor alpha responsive elements the journal of biological chemistry 270 37 21545 51 doi 10 1074 jbc 270 37 21545 pmid 7665567 bezouska k nepovím a horváth o pospísil m hamann j feizi t march 1995 cd 69 antigen of human lymphocytes is a calcium dependent carbohydrate binding protein biochemical and biophysical research communications 208 1 68 74 bibcode 1995bbrc 208 68b doi 10 1006 bbrc 1995 1306 pmid 7887967 santis ag lópez cabrera m hamann j strauss m sánchez madrid f july 1994 structure of the gene coding for the human early lymphocyte activation antigen cd69 a c type lectin receptor evolutionarily related with the gene families of natural killer cell specific receptors european journal of immunology 24 7 1692 7 doi 10 1002 eji 1830240735 pmid 8026529 s2cid 25826530 ziegler sf ramsdell f hjerrild ka armitage rj grabstein kh hennen kb farrah t fanslow wc shevach em alderson mr july 1993 molecular characterization of the early activation antigen cd69 a type ii membrane glycoprotein related to a family of natural killer cell activation antigens european journal of immunology 23 7 1643 8 doi 10 1002 eji 1830230737 pmid 8100776 s2cid 6360771 lópez cabrera m santis ag fernández ruiz e blacher r esch f sánchez mateos p sánchez madrid f august 1993 molecular cloning expression and chromosomal localization of the human earliest lymphocyte activation antigen aim cd69 a new member of the c type animal lectin superfamily of signal transmitting receptors the journal of experimental medicine 178 2 537 47 doi 10 1084 jem 178 2 537 pmc 2191117 pmid 8340758 hamann j fiebig h strauss m june 1993 expression cloning of the early activation antigen cd69 a type ii integral membrane protein with a c type lectin domain journal of immunology 150 11 4920 7 doi 10 4049 jimmunol 150 11 4920 pmid 8496594 s2cid 44371939 krowka jf cuevas b maron dc steimer ks ascher ms sheppard hw january 1996 expression of cd69 after in vitro stimulation a rapid method for quantitating impaired lymphocyte responses in hiv infected individuals journal of acquired immune deficiency syndromes and human retrovirology 11 1 95 104 doi 10 1097 00042560 199601010 00013 pmid 8528739 iafrate aj bronson s skowronski j february 1997 separable functions of nef disrupt two aspects of t cell receptor machinery cd4 expression and cd3 signaling the embo journal 16 4 673 84 doi 10 1093 emboj 16 4 673 pmc 1169669 pmid 9049297 vance ba bennett mj ward y gress rg kearse kp august 1999 distinct but dispensable n glycosylation of human cd69 proteins archives of biochemistry and biophysics 368 2 214 20 doi 10 1006 abbi 1999 1322 pmid 10441371 blázquez mv macho a ortiz c lucena c lópez cabrera m sánchez madrid f muñoz e september 1999 extracellular hiv type 1 tat protein induces cd69 expression through nf kappab activation possible correlation with cell surface tat binding proteins aids research and human retroviruses 15 13 1209 18 doi 10 1089 088922299310304 pmid 10480634 llera as viedma f sánchez madrid f tormo j march 2001 crystal structure of the c type lectin like domain from the human hematopoietic cell receptor cd69 the journal of biological chemistry 276 10 7312 9 doi 10 1074 jbc m008573200 hdl 11336 45350 pmid 11036086 natarajan k sawicki mw margulies dh mariuzza ra december 2000 crystal structure of human cd69 a c type lectin like activation marker of hematopoietic cells biochemistry 39 48 14779 86 doi 10 1021 bi0018180 pmid 11101293 liu x schrager ja lange gd marsh jw august 2001 hiv nef mediated cellular phenotypes are differentially expressed as a function of intracellular nef concentrations the journal of biological chemistry 276 35 32763 70 doi 10 1074 jbc m101025200 pmid 11438519 diament d brunialti mk romero ec kallas eg salomao r april 2002 peripheral blood mononuclear cell activation induced by leptospira interrogans glycolipoprotein infection and immunity 70 4 1677 83 doi 10 1128 iai 70 4 1677 1683 2002 pmc 127819 pmid 11895929 yoshimura c yamaguchi m iikura m izumi s kudo k nagase h ishii a walls af ra c iwata t igarashi t yamamoto k hirai k may 2002 activation markers of human basophils cd69 expression is strongly and preferentially induced by il 3 the journal of allergy and clinical immunology 109 5 817 23 doi 10 1067 mai 2002 123532 pmid 11994706 pisegna s zingoni a pirozzi g cinque b cifone mg morrone s piccoli m frati l palmieri g santoni a july 2002 src dependent syk activation controls cd69 mediated signaling and function on human nk cells journal of immunology 169 1 68 74 doi 10 4049 jimmunol 169 1 68 pmid 12077230 liu cc huang kj lin ys yeh tm liu hs lei hy october 2002 transient cd4 cd8 ratio inversion and aberrant immune activation during dengue virus infection journal of medical virology 68 2 241 52 doi 10 1002 jmv 10198 pmid 12210415 s2cid 21271659 foerster m haefner d kroegel c october 2002 bcl 2 mediated regulation of cd69 induced apoptosis of human eosinophils identification and characterization of a novel receptor induced mechanism and relationship to cd95 transduced signalling scandinavian journal of immunology 56 4 417 28 doi 10 1046 j 1365 3083 2002 01111 x pmid 12234263 s2cid 21934164 weigel g griesmacher a karimi a zuckermann ao grimm m mueller mm october 2002 effect of mycophenolate mofetil therapy on lymphocyte activation in heart transplant recipients the journal of heart and lung transplantation 21 10 1074 9 doi 10 1016 s1053 2498 02 00440 0 pmid 12398872 external links edit cd69 protein human at the u s national library of medicine medical subject headings mesh human cd69 genome location and cd69 gene details page in the ucsc genome browser v t e pdb gallery 1e87 human cd69 trigonal form 1e8i human cd69 tetragonal form 1fm5 crystal structure of human cd69 v t e proteins clusters of differentiation see also list of human clust...
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